Article

Natriuretic Peptide Receptor A as a Novel Target for Prostate Cancer

Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA.
Molecular Cancer (Impact Factor: 4.26). 05/2011; 10(1):56. DOI: 10.1186/1476-4598-10-56
Source: PubMed

ABSTRACT

The receptor for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPRA), is expressed in cancer cells, and natriuretic peptides have been implicated in cancers. However, the direct role of NPRA signaling in prostate cancer remains unclear.
NPRA expression was examined by western blotting, RT-PCR and immunohistochemistry. NPRA was downregulated by transfection of siRNA, shRNA and NPRA inhibitor (iNPRA). Antitumor efficacy of iNPRA was tested in mice using a TRAMP-C1 xenograft. Here, we demonstrated that NPRA is abundantly expressed on tumorigenic mouse and human prostate cells, but not in nontumorigenic prostate epithelial cells. NPRA expression showed positive correlation with clinical staging in a human PCa tissue microarray. Down-regulation of NPRA by siNPRA or iNPRA induced apoptosis in PCa cells. The mechanism of iNPRA-induced anti-PCa effects was linked to NPRA-induced expression of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine over-expressed in PCa and significantly reduced by siNPRA. Prostate tumor cells implanted in mice deficient in atrial natriuretic peptide receptor A (NPRA-KO) failed to grow, and treatment of TRAMP-C1 xenografts with iNPRA reduced tumor burden and MIF expression. Using the TRAMP spontaneous PCa model, we found that NPRA expression correlated with MIF expression during PCa progression.
Collectively, these results suggest that NPRA promotes PCa development in part by regulating MIF. Our findings also suggest that NPRA is a potential prognostic marker and a target for PCa therapy.

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Available from: Katherine L Meyer-Siegler
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    • "The receptor for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), have been reported to be expressed in lung cancer, prostate cancer, ovarian cancer. NPR-A expression and signaling is important for tumor growth, its deficiency protect C57BL/6 mice from lung, skin, and ovarian cancers, and these result suggest that NPR-A is a new target for cancer therapy [4] [5]. "
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    ABSTRACT: The receptors for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), have been reported to be expressed in lung cancer, prostate cancer, ovarian cancer. NPR-A expression and signaling is important for tumor growth, its deficiency protect C57BL/6 mice from lung, skin, and ovarian cancers, and these result suggest that NPR-A is a new target for cancer therapy. Recently, NPR-A has been demonstrated to be expressed in pre-implantation embryos and in ES cells, it has a novel role in the maintenance of self-renewal and pluripotency of ES cells. However, the direct role of NPR-A signaling in gastric cancer remains unclear. NPR-A expression was downregulated by transfection of shRNA. The proliferation of gastric cancer cells was measured by Hoechst 33342 stain. Cell proliferation and invasion were determined via BrdU and transwell assays, respectively. Down-regulation of NPR-A expression by shNPR-A induced apoptosis, inhibited proliferation and invasion in AGS cells. The mechanism of shNPR-A-induced anti-AGS effects was linked to NPR-A-induced expression of KCNQ1, a gene to be overexpressed in AGS and significantly reduced by shNPR-A. Collectively, these results suggest that NPR-A promotes gastric cancer development in part by regulating KCNQ1. Our findings also suggest that NPR-A is a target for gastric cancer therapy.
    Full-text · Article · Oct 2014 · International Journal of Clinical and Experimental Medicine
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    • "Vesely reported natriuretic peptides including ANP inhibit proliferation of various cancer cells and tumor growth, and NPR-A is expressed in various cancer cells [51], but he did not investigate the direct role of NPR-A in tumorigenesis. Recently the direct role of NPR-A signaling in tumorigenesis has been clarified by animal model, interfering RNA, Western blot and immunohistochemistry [8,9]. "
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    ABSTRACT: The receptor for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), has been reported to be expressed in lung cancer, prostate cancer and ovarian cancer. NPR-A expression and signaling is important for tumor growth; its deficiency protects C57BL/6 mice from lung, skin and ovarian cancers. This suggests that NPR-A is a new marker and a new target for cancer therapy. Recently, NPR-A has been demonstrated to be expressed in pre-implantation embryos and in embryonic stem cells, which has a novel role in the maintenance of self-renewal and pluripotency of embryonic stem cells. A nanoparticle-formulated interfering RNA for NPR-A attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH2-terminal peptide of the ANP prohormone which downregulates NPR-A expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. These results suggest that NPR-A is involved in tumorigenesis and a new target for cancer therapy. This review focuses on structure, abnormal functions and carcinogenic mechanisms of NPR-A to investigate its role in tumorigenesis.
    Full-text · Article · Jun 2014 · World Journal of Surgical Oncology
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    • "Prior research indicates that NPRA is highly or lowly expressed on cells in many different tissues of various organ systems or cancers except for esophageal squamous carcinoma. Wang’s group found that NPRA is abundantly expressed in human prostate cancer (PCa) cells and tumorigenic mice, and that downregulation of NPRA can induce apoptosis in PCa cells; however, the expression of NPRA in nontumorigenic prostate epithelial cells is much lower than in PCa cells [16]. In experiments on NPRA downregulation, NPRA-deficient C57BL/6 mice showed significant anti-cancer activity [14], and NP73-120, which is the NH2-terminal peptide of ANP pro-hormone that can restrain the expression of NPRA, was used to investigate the effect in human lung cancer tumorigenesis. "
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    ABSTRACT: Background The natriuretic peptide receptor-A (NPRA) has been investigated as a receptor of natriuretic peptides in the cardiovascular system. In this study, however, we analyze the expression status of NPRA and the relationship with tumor invasion in esophageal squamous cell carcinoma (ESCC) for the first time. Methods Western blots were used to examine the expression status of protein in human ESCC cell lines. Then, we used immunohistochemistry to detect the expression of NPRA in 45 ESCC specimens and 40 corresponding nontumor tissues. The clinical data were analyzed through statistical methods. Sh-RNA-NPRA was transfected into Eca109 cells to detect the relationship between NPRA and cell invasion through transwell assays. Results In esophageal squamous cells, the expression of NPRA was strongly detected in the cytoplasm, while undetectable or very weak in the nucleus. The positive rates of NPRA in cancer tissues are significantly higher than that in nontumor tissues (P <0.05). Clinicopathological analyses revealed that increased NPRA expression correlated with differentiation and TNM stage (P <0.05), while it showed no statistically significant association with age, gender, and lymph node metastasis. In analysis of prognosis, we found that highly.Transwell assays showed that NPRA promoted Eca109 cell migration and invasion in vitro and may be involved in MMP2 and MMP9 activation. Conclusions NPRA protein is highly expressed in ESCC tissues and could promote Eca109 cell migration and invasion in vitro.
    Full-text · Article · May 2014 · World Journal of Surgical Oncology
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